PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Mueller, Martin; Zhou, Jichun; Yang, Lihua; Gao, Yuan; Wu, Fengyuan; Schoeberlein, Andreina; Surbek, Daniel; Barnea, Eytan R.; Paidas, Michael J.; Huang, Yingqun

doi:10.1073/pnas.1411674111

Cited by 64 publications

(120 citation statements)

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“…10 The neuroprotective property of sPIF was further underscored by its ability to mitigate neuronal loss and microglial activation in a rat model of perinatal brain injury. 11 The neuroprotective effects were attributed, at least in part, to sPIF's ability to downregulate microRNA let-7 in the injured brain. Abundantly expressed in the central nervous system (CNS), let-7 released from dying cells during brain injury induces neuronal death, exacerbating CNS damage.…”

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confidence: 99%

“…12,13 sPIF inhibited the biogenesis of let-7 in both neuronal and immune cells through Toll-like Receptor 4 (TLR4). 11 As PIF imparts multitargeted effects, 10 it is almost certain that inhibiting let-7 is not the only mechanism of PIF action.…”

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confidence: 99%

“…PKA/PKC signaling is downstream of TLR4, 14,15 and TLR4 was required for sPIFinduced neuroprotective effects. 11 PKA/PKC are important signaling molecules in a variety of cellular functions, including cell growth and differentiation, neuronal plasticity and cellular response to hypoxia-ischemia. [16][17][18][19] Mechanistically, PKA/ PKC activation leads to phosphorylation of serine and threonine residues on target proteins, thereby modulating protein stability, protein-protein interactions and catalytic activity.…”

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confidence: 99%

“…Given that sPIF induces global alterations in gene expression, it is highly likely that sPIF facilitates neuronal survival beyond targeting microRNA let-7. 9,11 To evaluate the neuroprotective potential of sPIF, we induced brain injury in neonatal rats at P2 (Figure 1a). This time point matches ongoing neuronal development.…”

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confidence: 99%

“…28 We focused on evaluating regions containing motor and somatosensory cortices, as injury in these regions between the rhinal sulcus and the cingulum causes distinctive neuropathological alterations. 11,27,29 We examined the position of upper (CUX1-positive) and deeper (CUX1-negative) neurons in the cortex (Figure 1b). CUX1 is a well-defined molecular marker of upper-layer neurons (cortical layers II-IV).…”

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PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

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A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

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PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

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Genetics of Early Miscarriages

Vaiman

2016

Encyclopedia of Life Sciences

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Early miscarriage or early pregnancy loss (EPL) is defined by an embryonic foetal loss occurring before 13 weeks of gestation. In this article, we focus on the genetics of this complex human disease from studies of human patients, sometimes including foetal losses occurring before 20 weeks. Most of the mouse studies on EPL are based on gene invalidation experiments having much wider and pleiotropic effects than a mere defect of implantation or placental development, and therefore they will not be analyzed here. In addition, many good reviews are already available on gene polymorphisms relevant to early miscarriage and are only briefly summarised here. We develop more in‐depth aspects connected to microRNA and copy number variations with EPL, issues that have been much less reviewed in the past. Key Concepts Early pregnancy loss is a complex multifactorial disease, leading to embryo loss in an estimated >70% of the fertilisation events in humans. Besides chromosome anomalies, detected by cytogenetics or CGH arrays (array‐based comparative genomic hybridisation), gene variants are associated with an increased risk of pregnancy loss. These genes may be regulators of immune response including cytokines, modulators of the coagulation cascade, equilibrators of the oxidative stress or, rarely, genes involved in chromosome segregation at meiosis or mitosis. Other genes may be found by genome‐wide association studies. Recent novel studies are developing on the impact of epigenetic regulators (essentially microRNAs) on miscarriages. These can be relevant markers to categorise gene expression deregulation in pregnancy losses.

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Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus—harvesting the power of omic technology, biomarkers and in vitro or in vivo models to facilitate the treatment of thrombosis

Ornaghi

Mueller

Barnea

et al. 2015

Birth Defects Research Pt C

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Maternal thromboembolism and a spectrum of placenta-mediated complications including the pre-eclampsia syndromes, fetal growth restriction, fetal loss, and abruption manifest a shared etiopathogenesis and predisposing risk factors. Furthermore, these maternal and fetal complications are often linked to subsequent maternal health consequences that comprise the metabolic syndrome, namely, thromboembolism, chronic hypertension, and type II diabetes. Traditionally, several lines of evidence have linked vasoconstriction, excessive thrombosis and inflammation, and impaired trophoblast invasion at the uteroplacental interface as hallmark features of the placental complications. "Omic" technologies and biomarker development have been largely based upon advances in vascular biology, improved understanding of the molecular basis and biochemical pathways responsible for the clinically relevant diseases, and increasingly robust large cohort and/or registry based studies. Advances in understanding of innate and adaptive immunity appear to play an important role in several pregnancy complications. Strategies aimed at improving prediction of these pregnancy complications are often incorporating hemodynamic blood flow data using non-invasive imaging technologies of the utero-placental and maternal circulations early in pregnancy. Some evidence suggests that a multiple marker approach will yield the best performing prediction tools, which may then in turn offer the possibility of early intervention to prevent or ameliorate these pregnancy complications. Prediction of maternal cardiovascular and non-cardiovascular consequences following pregnancy represents an important area of future research, which may have significant public health consequences not only for cardiovascular disease, but also for a variety of other disorders, such as autoimmune and neurodegenerative diseases.

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PreImplantation factor promotes neuroprotection by targeting microRNA let-7

Cited by 64 publications

References 62 publications

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

Genetics of Early Miscarriages

Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus—harvesting the power of omic technology, biomarkers and in vitro or in vivo models to facilitate the treatment of thrombosis

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